Abstract For reasons that remain unknown, sleep is essential for the reversal of deficits in cognition and performance that accumulate with increased severity during protracted wake. One of the most robust and reliable features of sleep is a reduction of cerebral metabolism, manifested by a decline in brain temperature and a decline in brain glucose and oxygen utilization, relative to wake. It stands to reason that the metabolic down state is essential for the restorative function of sleep, yet the biochemical basis for this relationship is uncertain. Oxidative metabolism of glucose fuels neuronal activity. Postmortem assays indicate that protracted wake produces an accumulation of oxidative stress in the brain. We hypothesize that reduced glucose utilization in sleep reverses a metabolically-driven shift in the redox status (the balance of oxidation and reduction reactions) of parvalbumin-positive neurons caused by the high metabolic demand of these cells in the waking brain. We further hypothesize that this function of sleep is facilitated in part by an extracellular matrix structure known as perineuronal nets, which serve to buffer against oxidative stress in metabolically vulnerable neurons. To address these hypotheses, we will perform a systemic pharmacological manipulations (the oxidation/reduction reaction substrate nicotinic adenine dinucleotide) known to affect the brain?s capacity to withstand oxidative stress. We will also assess perform brain region-specific depletion of perineuronal nets. We will assess the effects of these manipulations, and those of sleep/wake cycle manipulations, on cellular redox status markers, both in real- time in vivo using intravital microscopy, and post mortem by coupling oxidation assays with cell type-specific immunochemical markers and histochemical assessment of perineuronal net intensity. We will additionally measure the effects of the experimental manipulations on electroencephalographic markers for brain fatigue and sleep need. The anticipated results will establish a causal interrelationship between sleep/wake cycles and brain redox status, and will identify brain oxidation/reduction reactions as a target for both diagnostic inquiry and therapeutic intervention in the face of sleep insufficiency. 1